Acute kidney injury (AKI) occurs in 20% of hospitalized patients and increases the risk of death. Death from AKI is typically due to systemic complications. Respiratory failure is an especially detrimental complication of AKI and can increase patient mortality to 60 to 80%. The reason AKI causes respiratory failure is unclear, but may be due to inflammation. Our data in mice demonstrate that AKI is a pro-inflammatory state that is characterized by increased serum proinflammatory mediators (cytokines) at 2 hours and lung injury that occurs by 4 hours. Lung injury after AKI in mice is characterized by lung neutrophil accumulation and lung capillary leak. In this grant, we propose that AKI is a proinflammatory event that normally initiates a counter inflammatory response via production of IL-10. IL-10 is a potent anti-inflammatory cytokine that inhibits production of proinflammatory mediators. We suggest that cells known as macrophages are the key source of IL-10 production after AKI. Our overall hypothesis is that IL-10 production in macrophages is necessary to contain proinflammatory cytokine production and lung injury after AKI. Studies to understand the normal counter inflammatory response after AKI in mice are proposed with the goal of identifying therapies that facilitate resolution of inflammation and lung injury after AKI. In Specific Aim 1, we will determine whether macrophages in the spleen increase IL-10 production after AKI. We hypothesize that macrophages are the major source and that IL-6 is a key mediator of this response. GFP reporter mice (IL-10 producing cells are GFP positive) and flow cytometry will also be used to determine if splenic macrophages produce IL-10. The role of IL-6 in mediating splenic IL-10 production will be tested in vivo and in vitro. n Specific Aim 2, we will determine if IL-10 is necessary to reduce proinflammatory cytokine production and limit lung injury in AKI. We hypothesize that IL-10 limits proinflammatory cytokine production and lung injury after AKI. To determine the beneficial role of IL-10 after AKI serum cytokines, organ cytokine production, and lung injury will be determined in AKI with IL-10 deficiency. The therapeutic potential of IL-10 in AKI will be tested in wild type and IL-10 deficiet mice; IL-10 will be administered prior to injury or at times after injury to determine if IL-10 may be a potential treatment. In Specific Aim 3, we will determine if IL-10 producing macrophages facilitate resolution of AKI- mediated lung injury. We hypothesize that IL-10 producing macrophages limit lung injury after AKI. The role of IL-10 producing macrophages in AKI will be assessed in mice with deletion of IL-10 in macrophages; administration of IL-10 producing or deficient macrophages will also be performed.